PL201216B1 - Devices for the delivery of drugs having antiprogestinic properties - Google Patents

Abstract

This invention relates to a device for the controlled release over a prolonged period of time of a drug having antiprogestinic properties, said device comprising - a core comprising said drug,- optionally a membrane encasing said core, wherein said core and/or membrane is made of a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer. The device is characterized in that - the elastomer composition comprises poly(alkylene oxide) groups and that the poly(alkylene oxide) groups are present in the elastomer or polymer as alkoxy-terminated grafts of polysiloxane units, or as blocks, the said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.

Description

REPUBLIC POLAND (12) PATENT DESCRIPTION (19) PL (21) Application number: 355994 (11) 201216 (13) B1 (22) Date of notification: 21/11/2000 (51) Int.Cl. A61K 9/22 (2006.01) (86) Date and number of the international application: 21/11/2000, PCT / FI00 / 01013 A61K 31/56 (2006.01) patent Office (87) Date and publication number of the international application: Polish Republic 2001-07-05, WO01 / 47490 PCT Gazette No. 27/01

Device for the controlled release of a drug for an extended period of time with anti-progestogenic properties (73) The patent holder:

BAYER SCHERING PHARMA OY, Turku, FI (30) Priority:

12/23/1999, US, 09 / 472,126 (43) Application announced:

May 31, 2004 BUP 11/04 (45) The following was announced about the grant of the patent:

31.03.2009 WUP 03/09 (72) Inventor (s):

Harri Jukarainen, Turku, FI Toomi Markkula, Sale, GB Juha Ala-Sorvari, Turku, FI Pirkko Lehtinen, Piispanristi, FI Jarkko Ruohonen, Vanhalinna, FI Timo Haapakumpu, Littoinen, FI (74) Agent:

Ostrowska Elżbieta, POLSERVICE,

Kancelaria Rzeczników Patentowych Sp. z o.o.

⁽⁵⁷⁾ The present invention relates to a controlled release device with antiprogestogenic properties over an extended period of time, the device consisting of a core containing said drug, or a membrane surrounding the core, the core and / or the membrane is made of a siloxane-based elastomer composition comprising at least one elastomer and optionally a non-cross-linked polymer, the elastomer composition comprising poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer or polymer as strains of polysiloxane units containing a terminal alkoxy group, either as blocks, the strains or blocks being linked to the polysiloxane units by silicon-carbon bonds or as a mixture of these species, the antiprogestagens being the compounds specified in the description of the invention.

PL 201 216 B1

Description of the invention

The present invention relates to a device for the controlled release over an extended period of time of a drug having anti-progestogenic properties. Specifically, they are implantable devices, intrauterine or intravaginal devices, or transdermal devices for delivering said drug at the desired rate and over an extended period of time.

In this specification, publications and other materials are provided as references to illustrate the background of the invention and, in specific instances, to provide additional details relating to the practice of the invention.

The use of drug delivery devices that allow the drug to be released slowly in the body at a controlled rate over an extended period of time to achieve the desired physiological or pharmacological effect has proven beneficial in many areas of medicine. The primary advantage of using sustained-release compositions is that otherwise many therapeutic agents would be rapidly metabolized or released from the patient's body, thereby necessitating frequent drug administration to maintain a therapeutically effective drug concentration.

Various methods have been described in the literature, including physiological modification of absorption or excretion, solvent modification, chemical modification of the drug, absorption of the drug onto an insoluble vehicle, the use of suspensions, and implant pills. Other methods include mixing the drug with a carrier such as waxes, oils, fats, and soluble polymers that gradually break down in the environment, releasing the drug. Much attention has been given to a reservoir type device, that is, a device in which the medicament is enclosed within the container, with or without a solvent or carrier, which allows the medicament to flow out of the reservoir.

Yet another type of drug delivery device is the type of device in which the drug is dispersed in the polymer and from which the drug is released either by decomposition of the polymer or by passage of the drug through a polymer membrane.

In principle, any polymer can be used as the carrier as long as it is biocompatible. However, the kinetics of drug release from the polymeric delivery system depends on the molecular weight, solubility, diffusion constant, and charge of the active ingredient, as well as the properties of the polymer, the percentage of drug loading, the distance the drug must diffuse through the body of the device to reach its surface area, and any property of any kind. matrix or membrane coating. The importance of these factors, in conjunction with the pharmacological, toxicological and therapeutic goals, requires that the design of a polymeric device for a specific agent be carefully designed.

Examples of commonly used polymeric materials include elastomers such as polysiloxanes, ethylene / vinyl acetate (EVA) copolymers, and dimethylsiloxanes and methylvinylsiloxanes copolimmers. The structural integrity of the material can be enhanced by adding a particulate material such as silica or diatomaceous earth.

The device made of EVA has some shortcomings. The materials are rather stiff and inelastic and are therefore rather inconvenient for use as subcutaneous implants.

Polysiloxanes, especially poly (dimethylsiloxane) (PDMS), are particularly suitable for use as a drug permeation rate-regulating membrane or matrix in various drug forms, particularly in implants, intrauterine devices and vaginal rings.

Polysiloxanes are physiologically inert and a wide range of drugs are capable of penetrating polysiloxane membranes, which also have the required strength properties.

It is known from the literature that the addition of poly (ethylene oxide) groups, i.e. PEO groups, to the PDMS polymer can increase the permeation rate of drugs. Membranes containing PEO and PDMS and the permeation of various steroids through these membranes are described in Katherine L. Ulman et al., Journal of Controlled Release 10 (1989) pages 251-260. Increasing the amount of PEO in the block polymer is reported to lead to an increase in the penetration of hydrophilic steroids, while a decrease in the penetration of lipophilic steroids.

However, the block copolymer described in the publication is very complicated in its structure and it is complicated to obtain, and therefore it will not be easy to manufacture it on a larger scale.

Subcutaneous contraceptive implants are known in the art and are described, for example, in United States Patent Nos. 4,957,119, 5,088,505, 5,035,891, 5,565,443 and 5,633,000. Matrix-type implants made of poly (dimethylsiloxanes) are described in the literature (Nash, Robertson et al., Contraception 18, 1978, page 367).

PL 201 216 B1

EP 710 491 A discloses a device consisting of a core and a membrane for the controlled release of drugs, in particular hormonal (female contraceptives) of the 19-norprogesterone type. A preferred polymer is poly (dimethylsiloxane). This publication differs from the present invention in that the hormones are different and the polymers are different from those used herein. Therefore, one skilled in the art would not associate the present application with, for example, the above cited Ulman et al, as the molecules are different and the antiprogestagens in the present invention are estradienes with large substituents.

The commercially available Norplant® system is an implant having a core containing a synthetic progestin-levonorgestrel as active ingredient, and the core is surrounded by a poly (dimethylsiloxane) silicone elastomer membrane. A special preparation of this type is Jadelle® in which the core is a poly (dimethylsiloxane) based matrix with levonorgestrel dispersed therein. The membrane is an elastomer made of PDMS and silica filler, which, apart from giving the membrane the necessary strength properties, slows down the penetration of the active ingredient through the membrane.

U.S. Patent No. 3,279,996 (Long et al.) Discloses an implant that contains an active substance surrounded by a polysiloxane membrane.

In Dutch Patent No. 167,850 (Zaffaroni), an implant is described in which the active substance is embedded in a polymer and this polymer loaded with the active substance is surrounded by a polymeric membrane which completely controls the release rate. However, the size, degree of rigidity and duration of the release of the contraceptive substance are not practical for these implants.

US Patent No. 3,854,480 describes a drug delivery device, such as an implant, for releasing a drug at a controlled rate over an extended period of time. The device has a core matrix in which the drug is dispersed. The core is surrounded by a membrane that is insoluble in body fluids. The core matrix as well as the membrane are permeable to the drug by diffusion. The core and membrane materials are selected such that the drug diffuses through the membrane at a slower rate than through the core matrix. In this way, the membrane controls the rate of drug release. As the polymer suitable for the core matrix, poly (dimethylsiloxane) is mentioned, and as a suitable polymer for the membrane, polyethylene and ethylene vinyl acetate (EVA) copolymer are mentioned.

US Patent No. 5,660,848 discloses a subcutaneously implantable drug delivery device that includes a centrally positioned core extending in an axial direction and having an outer surface and opposing ends. The core comprises a matrix with a therapeutically effective amount of a drug suitable for subcutaneous administration predominantly uniformly dispersed in the polymeric backing material: an intermediate polymeric layer surrounds the surface of the centrally located core and an outer polymeric layer surrounds the intermediate layer, the intermediate layer controlling the rate of diffusion of the drug from the core centrally located to the outer layer. In preferred embodiments, the drug is a contraceptive: both the polymeric backing material and the polymeric outer layer comprise poly (dimethylsiloxane) and the intermediate layer comprises a porous material such as cellulose.

Several types of vaginal rings have been described in the patent and non-patent literature, such as: U.S. Patent Nos. 4,012,496 and 4,155,991 (both Schopflin et al.), 4,292,965 (Nash), 3,545,439 (Duncan), 3,920,805 (Roseman), 3,991,760 and number 3,995,634 (both patents granted to Drobish and others),

3,995,633 (Gougen), 4,250,611 and 4,286,587 (both patents granted to Wong), 4,596,576 (de

Nijs); in International Publication No. WO95 / 00199 (Lehtinen et al.); and in Contraception 19, pages 507-516 (1979), (Jackanicz).

Implants or intravaginal devices for the delivery of agents with antiprogestinic properties are generally disclosed in US Pat. US with numbers 5,516,769, 5,521,166, 5,439,913, 5,622,943 and number 5,681,817.

It is an object of the invention to provide a delivery device for certain drugs having anti-progestogenic properties in order to deliver these drugs at a desired rate over an extended period of time.

PL 201 216 B1

In particular, it is an object of this invention to provide a drug delivery device in the form of an implant, intravaginal device, intracervical or intrauterine device or transdermal patch for the administration of said drug.

The object of the invention is particularly to provide a flexible and smooth drug release device which has a small cross-section and which is easy to insert and convenient to use.

Moreover, it is an object of the invention to provide a device whereby the drug release rate can be easily adjusted to the desired level.

The invention is based on the fact that elastomer compositions containing poly (alkylene oxide) groups in a polysiloxane release the active ingredient more quickly than polysiloxanes without these groups. Thereby, the desired delivery rate of the active agent can be achieved by using an elastomer composition (in form of a matrix or a membrane, or both) having the appropriate amount of poly (alkylene oxide) groups.

Thus, the present invention relates to a device for the controlled release over an extended period of time of a medicament having anti-progestogenic properties, the device comprising:

- a core containing this drug,

- optionally a membrane surrounding said core, wherein the core and / or the membrane are made of a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-cross-linked polymer, the elastomer composition comprising poly (alkylene oxide) groups, which poly ( alkylene oxide) are present in the elastomer or polymer as alkoxy terminated strains of polysiloxane units or as blocks, said strains or blocks being attached to the polysiloxane units via silicon-carbon bonds or as a mixture of these forms, the antiprogestagens being compounds selected from group including

11e - [(4- (dimethylamino) phenyl] -17e-hydroxy-17a- (1-propynyl) estra-4,9-diene-3-one (mifepristone), e - [(4- (dimethylamino) phenyl) - 17e-hydroxy-17a- (1-propynyl) -18-homoestra-4,9-dien-3-one, e - [(4- (dimethylamino) phenyl] -17e-hydroxy-17a- (1-propynyl) - 17a-homoestra-4,9,16-trien-3-one, e - [(4-dimethylamino) phenyl] -17a-hydroxy-17e- (3-hydroxypropyl) -13a-methylestra-4,9-dien-3 -one (onapristone), (Z) -11e - [(4-dimethylamino) phenyl)] - 17e-hydroxy-17a- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one (lylopristone ),

11e- (4-acetylphenyl) -17e-hydroxy-17a- (1-propynyl) -estra-4,9-dien-3-one, (Z) -11e- (4-acetylphenyl) -17e-hydroxy-17a (3-hydroxy-1-propenyl) estra-4,9-dien-3-one,

11e- (4-methoxyphenyl) -17e-hydroxy-17a-ethynyl estra-4,9-dien-3-one, (Z) -11e - [(4-dimethylamino) phenyl)] - 17e-hydroxy-17a- (3 -hydroxy-1-propenyl) estr-4-en-3-one,

4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) -oxime,

4- [17e-hydroxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) -oxime,

4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethylamino) carbonyl] oxime,

4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethoxy) carbonyl] oxime,

4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethylthio) carbonyl] oxime,

4- [17e-methoxy-17a- (ethoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethylthio) carbonyl] oxime,

4- [17e-hydroxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (n-propylthio) carbonyl] oxime, (Z ) -6 '- (4-cyanophenyl) -9,11a-dihydro-17e-hydroxy-17a- [4- (1-oxo-3-methylbutoxy) -1-butenyl) -4'H-naphtho- [3' , 2 ', 1': 10,9,11] ester-4-en-3-one, (Z) -6 '- (4-cyanophenyl) -9.11a-dihydro-17e-hydroxy-17a- [3 - (1-oxo-3-methylbutoxy) -1-propenyl) -4'H-naphtho- [3 ', 2', 1 ': 10.9.11] estra-4,15-dien-3-one, (Z) -6 '- (4-cyanophenyl) -9,11a-dihydro-17e-hydroxy-17a- (3-hydroxy-1-propenyl) -4'H-naphtha [3', 2 ', 1': 10,9,11] estra-4,15-dien-3-one, (Z) -6 '- (3-pyridinyl) -9,11a-dihydro-17e-hydroxy-17a- (3-hydroxy-1- propenyl) -4'H-naphtha [3 ',

2 ', 1': 10,9,11] estra-4,15-dien-3-one, e- (4-acetylphenyl) -17e-hydroxy-17a- (1,1,2,2,2-pentafluoroethyl ) estra-4,9-dien-3-one,

PL 201 216 B1

6 '- (acetyloxy) -9.11 a-dihydro-17e-hydroxy-17a- (1,1,2,2,2-pentafluoroethyl) -4'H-naphtha (3', 2 ', 1': 10 , 9,11] ester-4-en-3-one,

9,11a-dihydro-17e-hydroxy-6 '- (hydroxymethyl) -17a- (1,1,2,2,2-pentafluoroethyl) -4'H-naphtha [3', 2 ', 1': 10, 9,11] ester-4-en-3-one, e- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17a-chola-4,9,20-trien-3-one, e- (4-methoxyphenyl) -19,24-dinor-17,23-epoxy-17a-chola-4,9,20-trien-3-one, (Z) -11e, 19- [4- (3 -pyridinyl} -o-phenylene) -17e-hydroxy-17a- [3-hydroxy-1-propenyl) -4-androsten-3-one, (Z) -11e, 19- [4- (4-cyanophenyl} -o-phenylene) -17e-hydroxy-17a- [3-hydroxy-1-propenyl) -4androsten-3-one e- (4- (1-methylethenyl) phenyl] -17a-hydroxy-17e- (3 -hydroxypropyl) -13a-estra-4,9-dien-3-one, e- [4- (3-furanyl) phenyl] -17a-hydroxy-17e- (3-hydroxypropyl) -13a-estra-4.9 -dien-3-on,

4 ', 5'-dihydro-11e- [4- (dimethylamino) phenyl] -6-methylspiro [estra-4,9-diene-17e, 2' (3'H) -furan] -3-one,

4 ', 5'-dihydro-11e- [4- (dimethylamino) phenyl] -7e-methylspiro [estra-4,9-diene-17e, 2' (3'H) -furan] -3-one,

4-e, 17a-dimethyl-17e-hydroxy-3-oxo-4a, 5-epoxy-5a-androstane-2a-carbonitrile,

7a- [9- (4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -trien-3,17e-diol,

3- (4-chloro-3-trifluoromethylphenyl) -1- (4-iodobenzenesulfonyl) -1,4,5,6-tetrahydropyridazine, (R, S) -3- (4-chloro-3-trifluoromethylphenyl) -1- (4-iodobenzenesulfonyl) -6-methyl-1,4,5,6-tetrahydropyridazine,

3- (3,4-dichlorophenyl) -1- (3,5-dichlorobenzoyl) -1,4,5,6-tetrahydropyridazine,

3- (3,4-dichlorophenyl) -1- (2,5-dichlorobenzenesulfonyl) -1,4,5,6-tetrahydropyridazine,

7,8-dibromo-3,4-diazo-1,2,3,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) phenanthrene, and

7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (2,5-dichlorobenzenesulfonyl) phenanthrene.

Preferably, in the device according to the invention, the core is an elastomeric matrix, optionally made of the above-defined elastomer composition.

Preferably, in the device according to the invention, the membrane or matrix is made of an elastomer based on polysiloxane units containing poly (alkylene oxide) groups.

Preferably, in the device according to the invention, the poly (alkylene oxide) groups in the elastomer composition are poly (ethylene oxide) groups (PEO groups).

Preferably, in the device according to the invention, the polysiloxane groups have the formula: (SiR'RO) qSiR'R where some of the substituents R 'and R are:

- free groups which are the same or different, such as lower alkyl or phenyl in which case the alkyl or phenyl may be substituted or unsubstituted or a polyalkylene oxide group with terminal alkoxy groups of the formula -R3-O- (CHR -CH2-O) m-alk, in which alk is lower alkyl, suitably methyl, R is hydrogen or lower alkyl, R3 is C2-6-straight or branched alkylene and m is from 1 to 30;

- bonds formed between a hydrogen atom or an alkenyl group and another polymeric chain in the elastomer;

- optionally unreacted groups such as hydrogen, vinyl and alkenyl terminated vinyl; and

- q is a number from 1 to 3000.

Preferably, in the device according to the invention, the free groups R 'and R are lower alkyl, preferably methyl.

Preferably, in the device according to the invention, the poly (alkylene oxide) groups are present in the elastomer in the form of poly (alkylene oxide) blocks of the formula:

-R3O (CHRCH2O) mR4 or

-CH2CHR1COO (CHRCH2O) mCOCHR1CH2 in whose formulas:

R is hydrogen, lower alkyl or phenyl, R 1 is hydrogen or lower alkyl, R3 and R4 are the same or different straight chain or branched C2-6 alkylene groups and m is from 1 to 30.

PL 201 216 B1

Preferably, in the device of the invention, the elastomeric composition is made of two elastomers that intertwine with each other, in which case:

- the first elastomer comprises poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer as strains of polysiloxane units having an alkoxy terminus or as blocks, said strains or blocks being attached to the polysiloxane units via linkages silicon-carbon or a mixture of these forms; and

- the second elastomer is a siloxane based elastomer.

Preferably, in the device of the invention, the second elastomer is a poly (dimethylsiloxane) based elastomer, which optionally contains polyalkylene oxide groups.

Preferably, in the device of the invention, the optional poly (alkylene oxide) groups of the poly (dimethylsiloxane) based elastomer are present as strains of polysiloxane units having an alkoxy terminus or as blocks, in which case these strains or blocks are attached to the polysiloxane units via silicon-carbon bonds or a mixture of these forms.

Preferably, in the device according to the invention, the elastomeric composition is a blend which comprises:

- a siloxane based elastomer; and

- a linear polysiloxane copolymer which comprises poly (alkylene oxide) groups, in which case the poly (alkylene oxide) groups are present in the polymer in the form of strains of polysiloxane units containing an end alkoxy group or as blocks, said strains or blocks being attached to polysiloxane units through silicon-carbon bonds or as a mixture of these forms.

Preferably, in the device according to the invention, the matrix is enclosed in a membrane.

Preferably, in the device according to the invention, both the matrix and the membrane are made of an elastomer composition containing poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer or in the polymer as strains of end-alkoxy end-containing polysiloxane units or as blocks. wherein said strains or blocks are attached to the polysiloxane units via silicon-carbon bonds or as a mixture of these species.

Preferably, the device according to the invention is an implant, an intrauterine or intracervical device, an intravaginal or a transdermal device.

The invention is shown in more detail in the drawing, where:

Figure 1 shows the daily in vitro release of drug with antiprogestagenic properties from the implants described in Example 11 (device 1 marked with a diamond: 5 mm core PDMS based; device 2 marked with a square: 5 mm core based on the new elastomer composition; and device 3 marked with a triangle: 13 mm long core based on a new elastomer composition;

Figure 2 shows the daily in vitro release of a drug with anti-progestogenic properties from the intrauterine devices (IUDs) described in Example 12 (device 4 marked with a diamond: PDMS-based 19 mm core; device 5 marked with a square: 19 mm core based on novel). an elastomeric composition;

Figure 3 shows the daily in vitro release of drug with anti-progestogenic properties from the implants described in Example 13 (device 6 marked with a diamond: 15 mm long core based on PDMS; device 7 marked with square: 15 mm core based on the new elastomer composition;

Figure 4 shows the daily in vitro release of a drug with antiprogestogenic properties from the intrauterine devices (IUDs) described in Example 14 (device 8 marked with a diamond: PDMS-based core 19 mm; device 9 marked with a square: core 19 mm long. based on a new elastomer composition;

Figure 5 shows the daily in vitro release of an anti-progestogenic drug from the intrauterine devices (IUDs) described in Example 15 (device 10 marked with a diamond: PDMS-based 15 mm core; device 11 marked with a square: 15 mm core. based on a new elastomer composition;).

The term "elastomeric composition" can mean one single elastomer, in which case polysiloxane units that contain poly (alkylene oxide) groups are present in that elastomer.

PL 201 216 B1

According to another embodiment, the elastomer composition can be made of two elastomers which are braided one inside the other. In this case, the first elastomer comprises poly (alkylene oxide) groups so that the poly (alkylene oxide) groups are present in the elastomer either as alkoxy terminated strains of polysiloxane units or as blocks, said strains or blocks being attached to the siloxane units via silicon-carbon bonds. The poly (alkylene oxides) may also be present as a mixture of the forms mentioned. The second elastomer may be a siloxane based elastomer, in fact a poly (dimethylsiloxane) based elastomer. The latter elastomer may also contain poly (alkylene oxide) groups. These poly (alkylene oxide) groups may be present either as alkoxy terminated strains of poly (dimethylsiloxane) units or as blocks, said strains or blocks being attached to the poly (dimethylsiloxane) units via silicon-carbon bonds. The poly (alkylene oxides) may also be present as a mixture of the above-mentioned forms.

According to a third embodiment, the elastomeric composition may be a mixture that consists of a siloxane-based elastomer which is for example made of PDMS and at least one linear polysiloxane copolymer which comprises poly (alkylene oxide) groups. In this case, the poly (alkylene oxide) groups may be present either as alkoxy terminated strains of the polysiloxane units or as blocks, said strains or blocks being attached to the polysiloxane units via silicon-carbon bonds. These poly (alkylene oxides) groups can of course also be present in the form of a mixture of the forms mentioned above. In this embodiment, also the siloxane-based elastomer may contain poly (alkylene oxide) groups, in which case the poly (alkylene oxide) groups are present in the elastomer either as alkoxy terminated strains of polysiloxane units or as blocks, the strains or blocks of these being are attached to the polysiloxane units via silicon-carbon bonds.

The poly (alkylene oxides) can of course also be present in the form of a mixture of the above-mentioned forms.

Of course, the elastomer composition can also be made of the above two elastomers entangled inside each other and of at least one linear polysiloxane copolymer that contains poly (alkylene oxide) groups.

The poly (alkylene oxide) groups of the elastomer composition can be, for example, poly (ethylene oxide) groups (PEO groups).

The polysiloxane units of the elastomer composition are preferably groups of the formula:

- (SiR'RO) qSiR'R where some of R 'and R are:

- free groups which are the same or different and are lower alkyl or phenyl, which alkyl or phenyl groups may be substituted or unsubstituted, or a poly (alkylene oxide) group with terminal alkoxy groups of formula R3-O- (CRH -CH2-O) m-alk, where alk is lower alkyl, suitably methyl, R is hydrogen or lower alkyl, m is from 1 to 30 and R3 is straight chain or branched C2-6-alkylene;

- bonds formed between a hydrogen atom or an alkenyl group and another polymeric chain in the elastomer;

- optionally unreacted groups such as hydrogen, vinyl and alkenyl terminated vinyl; and

- q is a number from 1 to 3000.

The term "lower alkyl" means herein and generally in the description of the elastomeric composition, C1-6-alkyl.

The above-mentioned free groups R 'and R are respectively lower alkyl, preferably methyl.

The term "poly (alkylene oxide) group" means that the group consists of at least two alkyl ether groups sequentially linked to each other.

According to a preferred embodiment, the poly (alkylene oxide) groups present in the elastomer are blocks of the formula:

- (CH2) 2O (CRHCH2O) m (CH2) y or

-CH2CR1HCOO (CRHCH2O) mCOCR1HCH2-;

PL 201 216 B1 with the following formulas:

R is hydrogen, lower alkyl or phenyl;

R1 is hydrogen or lower alkyl; y is from 2 to 6; and m is from 1 to 30.

The elastomer composition suitably includes a filler, such as silica, to provide the membrane with sufficient stiffness.

The word "membrane" means the same as a film.

According to a preferred embodiment, the novel elastomer is obtained by cross-linking, in the presence of a catalyst, a vinyl-functional polymer component and a hydride-functional siloxane component.

By cross-linking is meant the addition reaction of a siloxane component containing hydride functional groups with a carbon-carbon double bond of a vinyl-functional polymer component.

According to another embodiment, the elastomer is obtained by cross-linking a polymer in the presence of a peroxide catalyst.

In this case, the vinyl and methyl groups react with each other and form carbon-carbon bonds. The network bond can also be formed between two methyl groups or between two vinyl groups.

In the case of cross-linking, the amounts of the components are preferably selected such that the ratio of the molar amounts of the reactive hydride groups and the reactive double bonds is at least 1.

The vinyl-functional polymer can be:

a) a polysiloxane containing vinyl functional groups of the formula:

R'-SiR'RO (SiR'RO) rSiR'R'R 'where:

R 'and R are the same or different and represent lower alkyl or phenyl, in which case the alkyl or phenyl may be substituted or unsubstituted and some of R' and / or R have been substituted with vinyl groups; and r is from 1 to 27,000; or

b) alkenyl end-group based polysiloxane block copolymer having the formula: T (AB) XAT (I) wherein:

A = - (SiR'RO) qSiR'R-, in which formula R 'and R are the same or different and represent lower alkyl or phenyl, in which case the alkyl or phenyl may be substituted or unsubstituted;

B is a poly (alkylene oxide) of formula:

-R3O (CRHCH2O) mR4 or

-CH2CR1HCOO (CRHCH2O) mCOCR1HCH2-; and

T stands for:

-R ¹¹ O (CRHCH2O) mR3 or

-CH2 = CR1COO (CRHCH2O) mCOCR1HCH2-;

in which these formulas:

R is hydrogen, lower alkyl or phenyl, R1 is hydrogen or lower alkyl, R3 and R4 are the same or different C2-6 alkylene straight chain or branched, ^R11 represents a C2-6- alkylene straight chain or branched, m is from 1 to 30, q is from 1 to 3000 and x is from 0 to 100; or

c) a random or block copolymer based on vinyl-functional polysiloxane, having the formula:

R'-SiR'RO (SiR'RO) r (SiR'RO) pSiR'R- R 'where:

PL 201 216 B1

- in the first repeat unit: R 'and R are the same or different and represent lower alkyl or phenyl, in which case said alkyl or phenyl may be substituted or unsubstituted and some of the substituents R' and / or R have been substituted with groups vinyl and r is from 1 to 27,000; and

- in the second repeating unit: R 'represents a lower alkyl or an alkoxy terminated poly (alkylene oxide) group of the formula -R3-O- (CRH-CH2-O) malk, wherein alk is lower alkyl, suitably methyl, R is hydrogen or lower alkyl, R3 is straight or branched C2-6-alkylene and m is from 1 to 30; or R 'is phenyl, in which case said alkyl or phenyl may be substituted or unsubstituted and R is lower alkyl or phenyl, in which case said alkyl or phenyl may be substituted or unsubstituted and p is from 1 to 5000; or

d) α, ω-dialkenylpoly (alkylene oxide) of the formula:

R ¹¹ -O- (CRHCH ₂ O) _m -R ¹² wherein R ¹¹ and R ¹² are the same or different C2-6 alkenyl groups, R is hydrogen or lower alkyl, and m is from 1 to 30; or

e) a mixture of at least two of the above-mentioned components a) - d).

If, as described above, the formula of a vinyl-functional polysiloxane copolymer is R'-SiR'RO (SiR'RO) r (SiR'RO) pSiR'R-R ', it should be noted that it is the general formula in which blocks in consecutive parentheses may appear in any order relative to each other. Furthermore, it is preferred that both the vinyl group and the alkoxy terminated poly (alkylene oxide) group are not bonded to one and the same silicon atom.

A component containing a hydride functional group can be:

a) a siloxane containing a hydride functional group, which may be linear, star, branched or cyclic; or

b) a siloxane-based block copolymer having hydride end groups of formula:

T (BA) XBT (II) where:

T = -H-SiR'RO (SiR'RO) qSiR'R-;

A = -SiR'R (SiR'RO) qSiR'R- in which formula R 'and R are the same or different and represent lower alkyl or phenyl, in which case the alkyl or phenyl may be substituted or unsubstituted;

B is a poly (alkylene oxide) of formula:

-R3O (CRHCH2O) mR4 or

-CH2CR1HCOO (CRHCH2O) mCOCR1HCH2 in whose formulas:

R is hydrogen, lower alkyl or phenyl, R1 is hydrogen or lower alkyl, R3 and R4 are the same or different straight or branched C2-6-alkylene groups, m is from 1 to 30, q is a number from 1 to 3000 and x is a number from 0 to 100; or

c) a mixture of the abovementioned components a) and b).

According to one embodiment, the hydride functional siloxane copolymer may be a linear copolymer, in which case it is represented by the formula:

R'-SiR'RO (SiR'RO) rSiR'RR 'wherein R' and R are the same or different and represent lower alkyl or phenyl, in which case said alkyl or phenyl may be substituted or unsubstituted and some of the substituents R 'and / or and R have been substituted with a hydrogen atom and r is a number from 1 to 27,000.

The vinyl-functional polymer component may contain a filler, suitably silica.

The catalyst used for the cross-linking is preferably a noble metal catalyst, most often a platinum complex in alcohol, xylene, divinylsiloxane or cyclic vinylsiloxane. Particularly suitable is the Pt (O) divinyl tetramethyldisiloxane complex catalyst.

PL 201 216 B1

An elastomer composition made of two elastomers is obtained by first forming a first elastomer and then forming a second elastomer by crosslinking in the presence of the first elastomer. Thereby the second elastomer will penetrate the first elastomer.

An elastomer composition comprising an elastomer and a linear polymer is prepared, for example, by mixing a vinyl-functional polymer component, a hydride-functional component, and a polymer that has no vinyl or hydride groups. During cross-linking, the vinyl-functional polymer component and the hydride-functional component form an elastomer, but a polymer component that does not contain these functional groups will not participate in the cross-linking reaction but will remain uncrosslinked inside the elastomer.

The device may be any device capable of delivering the active ingredient at a controlled rate over an extended period of time. Thus, the device may take a wide variety of shapes and forms for administering the active ingredient to various sites in the body. The invention includes external and internal drug delivery devices such as transdermal patches, implants for releasing a therapeutically effective agent into the body tissues, vaginal rings, and intracervical and intrauterine devices.

According to a preferred embodiment, the device is a subcutaneous implant, an intravaginal ring or an intrauterine device (IUD). According to the most preferred embodiments, the device is an implant for subcutaneous use or an intrauterine device.

The core of the device may consist of the antiprogestin active itself, for example in liquid or crystalline form, optionally in combination with other therapeutic active agents. Alternatively, the core may consist of the active ingredient or ingredients in admixture with pharmaceutically acceptable excipients.

Preferably, the core is an elastomeric matrix in which the drug is dispersed.

According to a particularly preferred embodiment, the core is made of a siloxane-based elastomer composition comprising at least one elastomer and optionally a non-cross-linked polymer. The elastomer composition comprises poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer or polymer as alkoxy terminated strains of polysiloxane units or as blocks, said strains or blocks being attached to the polysiloxane units via silicon bonds. carbon. The elastomer composition can also be a mixture of these forms.

While the device, such as an implant, for example, may be a conventional core consisting of an elastomeric matrix in which the active agent (s) is dispersed, the core is preferably enclosed in a membrane. The diaphragm is usually made of an elastomer.

According to a preferred embodiment, the membrane is made of a siloxane-based elastomer composition comprising at least one elastomer and optionally a non-crosslinked polymer. The elastomeric composition comprises poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer or polymer as alkoxy terminated strains of polysiloxane units or as blocks, said strains or blocks being attached to the polysiloxane units via silicon bonds. carbon. The elastomer composition can also be a mixture of these forms.

According to another alternative, the matrix can be made of the above-mentioned elastomer composition, while the membrane is made of conventional PDMS (i.e. PDMS containing no poly (alkylene oxide)). Alternatively, the membrane can be made of the above-mentioned elastomer composition, while the matrix is made of plain PDMS.

The implants of this invention can be manufactured according to standard methods. The therapeutically active agent is mixed with a core matrix polymer such as PDMS or with the components of the elastomer composition as defined above and then the above blend is shaped into the desired shape by compression, casting, extruding or other suitable method. A membrane layer can be applied to the core using known methods such as mechanical stretching, swelling, or dipping. See U.S. Patent Nos. 3,832,252, 3,854,480 and 4,957,119, which are hereby incorporated by reference.

A particularly useful method for the preparation of implants is disclosed in the Finnish patent specification No. FI 97947. This patent discloses an extrusion technology in which pre-fabricated active ingredient-containing rods are covered with an outer membrane. Each such bar is followed, for example, by another bar not containing the active ingredient. The formed string cuts

Where the bars do not contain the active agent. Thus, there is no need for special sealing of the implant ends.

The intrauterine device can be made using well-known technology. A preferred intrauterine device (IUD) or intracervical device is a commonly used T-shaped body made of a plastic material such as polyethylene. The shaped piece consists of an elongated member (shank) having at one end a cross member consisting of two wings.

When the device is placed in the uterus, the elongated member and the cross member form a T-shaped body. The device has a thread attached long enough to protrude from the cervical canal when the device is placed in the uterus. IUD devices have a drug reservoir disposed about the elongate member. The drug reservoir is preferably a matrix consisting of an elastomeric matrix with the active agent (s) dispersed therein. Preferably, the matrix is enclosed in a membrane. The diaphragm is usually made of an elastomer.

The drug reservoir positioned around the stem of the T-shaped body may be manufactured as the implant described above. Alternatively, the matrix may first be applied around the shaft and then closed with the membrane.

The matrix and the membrane of the drug reservoir applied to the IUD can be made of the same elastomers as the implants described above.

Compounds with anti-progestogenic properties useful in this invention will be considered to compete, at least to some extent, with the progesterone at its receptor and thereby counteract progesterone effects at the receptor level. These compounds may be relatively pure compounds with anti-progestogenic properties, that is, they do not exhibit any other significant hormonal activity. The compounds may also exhibit to some extent other hormonal activity, for example anti-androgenic and / or anti-glucocorticoid activity. According to this invention, also suitable are compounds having antiprogestinic properties and which are accompanied to some extent by gestagenic activity and which are characterized by an indirect McPhail score, between non-gestagenic antiprogestogenic compounds and progestagens. It is also known that compounds with antiprogestinic properties may inherently exhibit some estrogenic activity.

The anti-progestogenic compounds useful in this invention may be of steroidal or non-steroidal origin.

The compounds of formula I disclosed in WO 98/34947 are competitive progesterone antagonists which prevent progesterone from binding to its receptor. At the same time, there are no or minimal side effects, such as, for example, androgenic, estrogenic or antiglucocorticoid activity. The compounds can be used as contraceptives, to treat hormonal abnormalities, to initiate the menstrual cycle, and to induce labor. Further indications include hormone replacement therapy (WO-A 94/18983), treatment of pain associated with dysmenorrhea, endometriosis (EP-A 0 266 303) as well as treatment of fibroids.

The compounds described in this invention are also useful for the treatment of hormone dependent neoplastic diseases. Moreover, in combination with other active substances such as antiestrogens, the compounds described in this invention can be used for the treatment of hormone dependent tumors (EP-A 0 310 542) and for contraception (WO 96/19997). Without limiting the scope of this invention, antiestrogens can be, for example, tamoxifen, ICI 182.780, antiestrogens described in PCT / EP97 / 04517, and aromatase inhibitors such as fadrozole, formestane, letrozole, anastrozole or atamestane or any other therapeutically active substance with anti-estrogenic properties.

Many compounds with anti-progestogenic properties are also suitable for the prevention and / or treatment of osteoporosis.

Antiprogestogens in combination with, for example, gonadotropins, release a hormone analog that can be used to treat conditions that are dependent on ovarian estrogen, such as endometriosis, uterine leiomyoma, PMS (premenstrual syndrome) or DUB (disturbed uterine bleeding), in which this approach does not occur rapid decline in bone density, as is the case with GnRH analogues alone (US Patent No. 5,681,817). Agents with antiprogestogenic properties in combination with inhibitors of progesterone synthesis are suitable for the treatment of endometriosis, dysmenorrhea

And hormone dependent tumors (e.g., US Patent No. 5,795,881). Agents with antiprogestogenic properties in combination with estrogens for hormone replacement therapy in women.

Agents with antiprogestinic properties can also be used in combination with other hormones, progestins, mesoprogestins, or other therapeutically active compounds such as flutamide, hydroxyflutamide, prostaglandins, glucocorticoids, and the like.

The required dose of compounds with antiprogestogenic properties is known in the art. The appropriate dose range will depend on the particular condition being treated, the severity of the condition, the duration of treatment, the route of administration and the nature of the compound employed.

Examples include:

- compounds according to US Patent No. 5,753,655 for contraception, menopause, endometriosis, breast cancer, cycle synchronization, termination of pregnancy, induction of labor or osteoporosis: 1-500 mg / kg, preferably 10-100 mg / kg / day;

- mifepristone: 0.05-10 mg / kg, preferably 0.5-5.0 mg / kg / day;

- compounds according to US Patent No. 5,516,769 for fertility control without ovulation prevention: oral - 0.01-1 mg, depot - 0.05-0.5 mg; compounds according to US Patent No. 5,439,913 for contraception (by inhibiting the formation of mucus-secreting glands and the growth of the epithelium, implantation of the fertilized egg in the uterus is impossible, the dose is lower than inhibiting ovulation and lower than causing abortion): 0.2550 mg daily dose / implant, vaginal ring.

The desired daily dosage of the drug in vivo, for a particular condition to be treated, for a defined drug and route of administration, can be achieved with the device of the invention, particularly by altering the composition of the elastomeric matrix or membrane, or both, to contain the appropriate amount of polyalkylene oxide groups. Increasing the concentration of such groups in the device will increase the penetration of the drug. In addition to the amount of poly (alkylene oxide) groups in the elastomer, other parameters such as device dimensions and form, drug load, and the like will affect the daily dose release from the device. Some experiments, but to a limited extent, will be required to determine the most appropriate parameters for each combination. The examples disclosed below will assist in such experiments.

The invention is described in more detail below by means of examples.

Examples 1-10 describe the preparation of membranes made of various elastomer compositions.

Various types of elastomer compositions (A-J) have been prepared. The greatest number of types of prepared compositions were compositions differing in the amount of PEO. Elastomeric membranes representing various compositions were tested for the permeation rates of various drugs.

In the elastomeric compositions A-H described below, an addition reaction between vinyl groups and silylhydroxide groups was used to cross-link, that is, to generate a cross-linked structure. Serving as the cross-linking agent, the hydride-functional siloxane polymer contained at least two Si — H groups which react with the carbon-carbon double bond of the polymer to be cross-linked. Membranes made of elastomer compositions I and J were prepared using a peroxide crosslinking catalyst, in which case vinyl or methyl groups reacted to form carbon-carbon bonds. In all composition types, except for types A, D, F and H, a base polymer blend was first prepared, in which case all the vinyl group containing polymers and the fillers or the vinyl group containing polymers containing the filler were mixed together. Silica was used as the filler. Compositions of types A, D, F and H each had only one vinyl group-containing polymer and were therefore basic polymers to each other. The base polymer blend was divided into two parts I and II. The catalyst was added to part I, while the crosslinker and inhibitor were added to part II. Parts I and II were joined immediately prior to cross-linking. The resulting blend was cross-linked at a temperature above the decomposition temperature of the inhibitor and at which the cross-linking reaction took place at the desired rate.

The composition can also be made directly from the blend in one step, in which case the ingredients can be added in the following order: vinyl group containing polymers, inhibitor, catalyst and crosslinker.

The table below describes the elastomeric membranes of the various composition types and their starting components.

PL 201 216 B1

T a b e l a 1

Composition type Polymers containing vinyl groups in the base polymer blend Crosslinker AND Α, ω-divinyl ether poly (ethylene oxide) -poly (dimethylsiloxane) multiblock copolymer (PEO- (PDMŚ-PEO) n) Siloxane with hydride functional groups B (PEO- (PDMS-PEO) n) and a siloxane polymer containing a filler Siloxane with hydride functional groups C. (PEO- (PDMS-PEO) n) separately or together with a siloxane polymer with or without a filler Α, ω-bis- (dimethylhydrosilyl) poly (dimethylsiloxane) -poly (ethylene oxide) multiblock copolymer, alone or together with hydride functional siloxane D Α, ω-divinyl ether of poly (ethylene oxide) (PEODIVI) Siloxane with hydride functional groups E. PEODIVI and a siloxane polymer with or without a filler Siloxane with hydride functional groups F. PEO-Methylvinylsiloxane graft copolymer (PDMS-PEO graft copolymer) Siloxane with hydride functional groups G. PDMS-PEO graft copolymer and a siloxane polymer with or without a filler Siloxane with hydride functional groups H. Α, ω-diallyl ether poly (ethylene oxide) -poly (dimethylsiloxane) multiblock copolymer (APEO- (PDMS-APEO) n) Siloxane with hydride functional groups AND (PEO- (PDMS-PEO) n) and a siloxane polymer with or without a filler Peroxide J. PDMS-PEO graft copolymer with a siloxane polymer with or without a filler Peroxide

P r z k ł a d 1

An elastomeric membrane obtained from a composition of type A

Ingredients used to obtain an elastomeric membrane:

- PEO-PDMS α, ω-divinyl ether block copolymer, in which the amount of PEO was 27.0% by weight and the content of vinyl groups was 0.186 mmol / g,

- Silopren U Katalysatoren Pt-D platinum catalyst (Bayer AG), which contained a platinum-siloxane complex in a siloxane matrix containing vinyl groups, with the platinum content being 1% by weight and the vinyl group content being 0.5 mmol / g,

- crosslinking agent - copolymer a, (O-di (trimethylsilyl) dimethylsiloxane-hydromethylsiloxane (DMS-HMS) Siloprene U Vernetzer 730 (Bayer AG), in which the Si-H content was 7.1 mmol / g, the molecular weight was 2800 g / mol and the ratio of DMS groups to HMS groups was 1: 1,

- inhibitor - 1-ethynyl-1-cyclohexanol (ETCH, Aldrich), with a decomposition temperature of + 40 ° C.

The copolymer used as substrate (PEO (-PDMS-PEO) n) was obtained as follows:

50 g of anhydrous α, ω-divinyl polyethylene oxide (PEODIVI) ether with a molar mass of 268 g / mol was weighed into a three-necked flask. In addition, 129.87 g of α, ω-bis (dimethylhydrosilyl) poly (dimethylsiloxane) (PDMSDIH, M _n = 717 g / mol) and 30% by weight of toluene dried by distillation were weighed into the same vessel. Since the vinyl groups were present in excess (3 mol%) in the reaction, the vinyl groups were present at both ends in the final product, which was important for the subsequent cross-linking. The reaction solution was stirred on a magnetic stirrer plate at 200 rpm, while dried oxygen was passed through the solution to prevent catalyst deactivation. The reaction solution was heated to 50 ° C and then the catalyst (Pt (0) divinyl tetramethyldisiloxane complex) was added to the solution through the septum. The amount of platinum was 30 ppm, calculated from the amount of the starting materials. From now on

The course of the polymerization reaction was monitored by IR until the reaction was completed (loss of the Si-H peak at 2130 cm ^-1 ), which took about 4 hours. After completion of the polymerization, toluene was distilled from the solution by increasing the temperature to 65 ° C and by reducing the pressure to 5 hPa for a period of 1 hour.

In the preparation of the elastomer, two blends were first prepared - parts I and II. Part I contained PEO- (PDMS-PEO) n and the platinum catalyst. Part II contained PEO- (PDMS-PEO) n, a cross-linking agent, and an inhibitor. Parts I and II were combined by mixing immediately prior to cross-linking.

The amounts of ingredients in the final blend of the composition of this example to be crosslinked were as follows:

- PEO- (PDMS-PEO) base polymer n 94.87% by weight,

- platinum catalyst 0.1% by weight,

- crosslinking agent 5.00% by weight,

- inhibitor 0.03% by weight.

Part I was obtained using a chamber mixer. 5.489 g of base polymer and 0.011 g of platinum catalyst were weighed into a chamber mixer. The ingredients were mixed until the blend was homogeneous.

Before mixing with Part II, the crosslinker and the inhibitor were combined. The crosslinker and inhibitor mixture was prepared by weighing 0.059 g ETCH and 9.941 g Silopren U Vernetzer 730 into a glass vessel and then stirring the mixture in a water bath at + 37 ° C until the ETCH was completely dissolved in the crosslinker. The amount of inhibitor in the mixture was 0.59% by weight.

Part II was obtained using a chamber mixer. The jacket of the chamber mixer was cooled with circulating water below room temperature to prevent the frictional temperature rise above the inhibitor's decomposition temperature. 4.947 g of the PEO-PDMS block copolymer and 0.553 g of the mixture of crosslinker and inhibitor were weighed into the mixing chamber. The ingredients were mixed until a homogeneous mixture was obtained.

Parts I and II were brought together just before cross-linking by adding 5 g of Part I and 5 g of Part II to the mixing chamber of the chamber mixer. The ingredients were mixed until the blend was homogeneous. The mix was removed and vacuum applied to remove air bubbles. Four batches of 2 g of the blend were weighed and subjected to successive crosslinking in a hot press.

The weighed blend was placed between two FEP release membranes in the center of a circular metal mold 0.4 mm thick and 8 cm inside diameter. The mixture, together with the molds and FEP membranes, was placed between the pressing surfaces of the hot pressing press, which surfaces were preheated to a temperature of + 115 ° C. The surfaces were pressed together and held at a pressure of 200 bar (20 MPa) for 5 minutes. The pressure of the press was released and the membrane was allowed to cure at room temperature for 24 hours. Using a punch, cut out round pieces with a diameter of 22 mm, intended for testing, from the membranes.

P r z k ł a d 2

An elastomeric membrane obtained from a type B composition

Ingredients used to obtain an elastomeric membrane:

- the same PEO (-PDMS-PEO) n polymer as in example 1 was used, with the difference that the amount of PEO was increased to 28.0% by weight and the amount of vinyl groups was increased to 0.24 mmol / g by increasing the PEODIVI proportion in the synthesis of block copolymer,

- the same catalyst, cross-linking agent and inhibitor were used as in example 1.

The filler-containing siloxane polymer was a dimethylsiloxane-vinylmethylsiloxane copolymer (DMS-VMS) containing a silica filler, the molar mass Mn of which was 400,000 g / mol. The content of vinyl groups in the blend was 0.011 mmol / g. The polymer contained 36% by weight of silica mixed with this polymer, the silica was surface treated with α, ff> -bis (dimethylhydroxysilH) -poN (dimethylsiloxane) (M = 520 g / mol), the content of which in the blend was 12 % by weight.

The amounts of ingredients in the composition of this example were as follows:

- PEO (-PDMS-PEO) n 32.8% by weight,

- DMS-VMS copolymer containing silica filler 60.9% by weight,

- platinum catalyst 0.1% by weight,

PL 201 216 B1

- a cross-linking agent

- inhibitor

6.19 wt%, 0.03 wt%.

First, the base polymer blend was made in a chamber mixer. 4.2 g of PEO (-PDMS-PEO) n block copolymer and 7.8 g of DMS-VMS copolymer containing silica filler were weighed into the mixing chamber. The ingredients were mixed until the blend was homogeneous.

Part I was prepared in the same way as in Example 1.

Prior to mixing with Part II, the crosslinker and inhibitor were combined as in Example 1, except that the amount of ETCH weighed was 0.048 g and the amount of Silopren U Vernetzer 730 was 9.952 g. The amount of inhibitor in the blend was 0.48 wt%.

Part II was prepared as described in Example 1, except that 4.816 g of the base polymer blend was weighed and the amount of crosslinker and inhibitor mixture was 0.684 g.

Part I and Part II were combined as described in Example 1. Four batches of 2 g each were weighed and crosslinked sequentially in a hot press as described in Example 1.

P r z k ł a d 3

An elastomeric membrane obtained from a type C composition

Ingredients used to obtain an elastomeric membrane:

- the same PEO (-PDMS-PEO) n copolymer as in example 2 was used,

- the catalyst and the inhibitor were the same as in examples 1 and 2,

- dimethylsiloxane-vinylmethylsiloxane copolymer (DMS-VMS) was the same as in example 2,

- the crosslinker used was a PDMS - (- PEO-PDMS) n copolymer with an Si — H group content of 0.26 mmol / g and a PEO content of 23.6% by weight.

This crosslinker was obtained as follows:

40 g of anhydrous α, ω-divinyl polyethylene oxide (PEODIVI) ether with a molecular weight of 246.3 g / mol was weighed into a three-neck flask. In addition, 129.4 ga,? -Bis (dimethylsilylhydro) poly (dimethylsiloxane) (PDMSDIH, M _n = 717 g / mol) and 30% by weight of toluene dried by distillation were weighed into the same vessel. Since the dimethylsilylhydrate groups were present in excess (10 mol%) in the final product, dimethylsilylhydride groups were present at both ends in the final product. The reaction solution was stirred on a magnetic stirrer plate at 200 rpm, while dried oxygen was passed through the solution to prevent catalyst deactivation. The reaction solution was heated to 50 ° C, and then the catalyst (Pt (0) divinyl tetramethylsiloxane complex) was added to the solution through the septum. The amount of platinum was 30 ppm, calculated from the amount of the starting materials. From then on, the course of the polymerization reaction was monitored by the IR method until the reaction was completed (loss of the vinyl peak at 1600 cm ^-1 ), which took about 4 hours. After completion of the polymerization, toluene was distilled from the solution by increasing the temperature to 65 ° C and by reducing the pressure to 5 hPa for a period of 1 hour.

The amounts of ingredients in the composition of this example were as follows:

- PEO- (PDMS-PEO) n 1.10% by weight,

- DMS-VMS containing silica filler 85.50% by weight,

- platinum catalyst 0.10% by weight,

- crosslinker, α, ω-bis (dimethylhydrosilyl) PEO-PDMS copolymer 13.27 wt.%

- inhibitor 0.03% by weight.

First, the base polymer blend was made in a chamber mixer. 0.15 g of α, ω-vinyl ether-PEO-PDMS block copolymer and 11.85 g of DMS-VMS copolymer silica filler were weighed into the mixing chamber. The ingredients were mixed until the blend was homogeneous.

Part I was prepared as outlined in Example 1.

Prior to mixing with Part II, the crosslinker and inhibitor were combined as described in Example 1, except that the amount of ETCH weighed was 0.022 g and 9.978 g of PDMS- (PEO-PDMS) n block copolymer was weighed instead of Vernetzer 730. The amount of inhibitor in of the blend was 0.22% by weight.

Part II was prepared as described in Example 1, except that 4.04 g of the base polymer blend was weighed and the amount of crosslinker and inhibitor mixture was 11.46 g.

PL 201 216 B1

Part I and Part II were combined as described in Example 1. Four batches of the blend of 2.1 g each were weighed and crosslinked sequentially in a hot press as described in the example.

P r z k ł a d 4

An elastomeric membrane obtained from a D-type composition

Ingredients used to obtain an elastomeric membrane:

- poly (ethylene oxide) α, ω-divinyl ether (PEODIVI) (polyoxyethylene glycol divinyl ether, Aldrich, Mn = 240 g / mol), the content of vinyl groups determined by titration was 7.4 mmol / g,

- Gelest SIP 6831.0 catalyst - platinum-siloxane complex in xylene, with a platinum content of 2.25% by weight,

- the cross-linking agent and the inhibitor were the same as in example 1.

The amounts of ingredients in the composition of this example were as follows:

- PEODIVI 52.231% by weight,

- platinum catalyst 0.045% by weight,

crosslinker 47.694% by weight,

- inhibitor 0.030% by weight.

First, a mixture of the cross-linker and the inhibitor was prepared by following the procedure of Example 1, except that the inhibitor was weighed in an amount of 0.0063 g and the amount of cross-linker was 9.9937 g. The amount of inhibitor in the mixture was 0.063% by weight.

5.2231 g PEODIVI and 0.0045 g platinum catalyst were mixed together in a glass vessel. Then 4.772 g of the mixture of the crosslinker and the inhibitor were mixed with this mixture.

Eight batches of 0.8 g of the mixture were weighed into aluminum molds with a flat bottom 5 cm in diameter, equipped with a FEP membrane at the bottom. The molds were placed for 15 minutes under ² hPa vacuum. The test pieces were cut out of the elastomer obtained.

P r z k ł a d 5

An elastomeric membrane obtained from an E-type composition

Ingredients used to obtain an elastomeric membrane:

- PEODIVI - same as in example 4, DMS-VMS copolymer - same as in example 2.

- catalyst, cross-linking agent and inhibitor were the same as in example 1.

The amounts of ingredients in the composition of this example were as follows:

- PEODIVI 11.37% by weight,

- DMS-VMS copolymer 64.46% by weight,

- platinum catalyst 0.1% by weight,

- crosslinking agent 24.03% by weight,

- inhibitor 0.03% by weight.

First, a mixture of the cross-linker and the inhibitor was prepared by following the procedure of Example 1, except that the inhibitor was weighed in an amount of 0.0125 g and the amount of cross-linker was 9.9875 g. The amount of inhibitor in the mixture was 0.125% by weight.

1.138 g of PEODIVI and 6.446 g of DMS-VMS copolymer were mixed together in the mixing chamber. 0.01 g of platinum catalyst was added and the blend was stirred until homogeneous. 2.406 g of a mixture of the crosslinker and the inhibitor were then added and the blend was mixed until homogeneous.

Four batches of 2.1 g of the blend were weighed and subjected to successive crosslinking in the hot press as described in Example 1.

Example 6

An elastomeric membrane obtained from an F-type composition

Ingredients used to obtain an elastomeric membrane:

- PDMS-PEO graft copolymer, in which the concentration of vinyl groups was 0.0743 mmol / g and the PEO content was 1.28% by weight,

- the catalyst, the cross-linking agent and the inhibitor were the same as in composition A.

A graft copolymer was used which was obtained as follows:

600 g of octamethylcyclotetrasiloxane (D4), 9.28 g of poly (dimethylsiloxane) -poly (ethylene oxide) graft copolymer (Gelest, DBE-821, containing 80% w / w PEO), 6.18 g of dimethylvinylsilyl end blocked PDMS (group blocker) were weighed. ends, Bayer Silopren U2) and 3.1 g of tetramethyltetravinylcyclotetrasiloxane. The weighed chemicals were loaded

Into the reactor filled with nitrogen gas, and agitation was commenced. The internal temperature of the reactor was raised to 135 ° C, and then the catalyst (potassium siloxoxide, 0.9 ml, 20 ppm K ⁺ ) was added to the reaction solution. The viscosity of the reaction solution increased rapidly, and after 1 h from the adding of the catalyst was possible to deactivate the catalyst by increasing the pressure in the reactor (2 x 10 ³ mbar) for a period of 15 minutes by means of carbon dioxide. Then, light cyclic compounds 913 wt.%) Were removed from the reactor by distillation (10 hPa), 30 minutes, 135 ° C). Molecular weight of the product - Mn = 190,000 g / mol.

The amounts of ingredients in the composition of this example were as follows:

- base polymer - graft copolymer - PDMS-PEO 96.10% by weight,

- platinum catalyst 0.5% by weight,

- crosslinker 3.06% by weight,

- inhibitor 0.34% by weight.

The combination of the crosslinker and the inhibitor was made as described in Example 1, except that the amount of ETCH weighed was 1.0 g and the amount of Silopren U Vernetzer 730 weighed was 9.0 g. The amount of inhibitor in the mixture was 10% by weight.

9.61 g of the PDMS-PEO graft copolymer and 0.05 g of the platinum catalyst were mixed together. Then 0.34 g of a mixture of the crosslinker and the inhibitor was added and the blend was mixed until homogeneous.

Four batches of 2.1 g of the blend were weighed and subjected to successive crosslinking in the hot press as described in Example 1.

P r z k ł a d 7

An elastomeric membrane obtained from a G-type composition

Ingredients used to obtain an elastomeric membrane:

- the same PDMS-PEO graft copolymer as in example 6,

- the DMS-VMS copolymer was the same as in example 2,

- catalyst, crosslinking agent and inhibitor were the same as in example 1.

The amounts of ingredients in the composition of this example were as follows:

- PDMS-PEO graft copolymer 96.10% by weight,

- DMS-VMS copolymer 72.31% by weight,

- platinum catalyst 0.10% by weight,

- cross-linking agent 0.81% by weight,

- inhibitor 0.03% by weight.

The combination of the crosslinker and the inhibitor was made as described in Example 1, except that the amount of the weighed ETCH was 0.36 g and the amount of Silopren U Vernetzer 730 weighed was 9.64 g. The inhibitor content of the mixture was 3 6% by weight.

2.675 g of the PDMS-PEO graft copolymer and 7.231 g of the DMS-VMS copolymer which contained a filler were mixed together. 0.01 g of platinum catalyst was added and the blend was stirred until homogeneous. Then 0.084 g of a mixture of the crosslinker and the inhibitor was added and the mixture was mixed until homogeneous.

Four batches of 2.1 g of the blend were weighed and subjected to successive crosslinking in the hot press as described in Example 1.

P r z k ł a d 8

An elastomeric membrane obtained from an H-type composition

Ingredients used to obtain an elastomeric membrane:

- APEO- (PDMS-APEO) n copolymer, in which the amount of PEO was 10.3% by weight and the content of vinyl groups was 0.063 mmol / g,

- the catalyst was the same as in example 4,

- the inhibitor was the same as in example 1,

the crosslinker was a DMS-HMS copolymer which contained 22.5% by weight of methylhydrogen siloxane groups (Gelest).

APEO- (PDMS-APEO) n copolymer was obtained as follows:

Anhydrous poly (ethylene oxide) α, ω-diallyl ether (PEODIAL) was weighed into a three-necked flask, the molar mass of which was 520 g / mol (which was obtained by adapting the procedure disclosed in Mei-Hui, Yang, Laing-Jong, Li, and Tsang-Feng, Ho "Synthesis and Characterization of polymethylsiloxane / poly (ethylene glycol) monomethyl ether copolymers", J. Ch. Colloid & Interface Soc., 3 (17), 1994, pages 19-28) and α, ω-bis (dimethylsilylhydro) -poly (dimethylsiloxane) (PDMSDIH, M _n =

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6000 g / mol). The weight of PEODIAL was 1.38 g (Mn = 520 g / mol, 5.28 mmol of allyl groups) and the weight of PDMSDIH was 12 g (4.8 mmol of hydride groups), with the number of allyl groups being 10% greater than the number of groups hydride. As a result, it was ensured to obtain the end product blocked with α, ω-allyl ends.

In addition, 45% by weight (7.2 g) of toluene was weighed into the reaction vessel. The reaction solution was stirred on a magnetic stirrer plate at 200 rpm, while dried oxygen was passed through the solution to prevent catalyst deactivation. The reaction solution was heated to 60 ° C and then the catalyst (Pt (0) divinyl tetramethyldisiloxane complex) was added to the solution through the septum, one drop at a time. The amount of platinum was 50 ppm, calculated from the amount of the starting materials. Polymerization was conducted for 6 hours, after which completion of the polymerization was confirmed by IR (loss of the Si-H peak at 2130 cm ^- 1). In order to remove toluene by distillation, the temperature was raised to 65 ° C and the pressure was reduced to 5 hPa over a period of 30 minutes.

The amounts of ingredients in the composition of this example were as follows:

- APEO- (PDMS-APEO) n 94.68% by weight,

- platinum catalyst 0.5% by weight,

- crosslinker 4.7% by weight,

- inhibitor 0.12% by weight.

3.0 g of APEO- (PMDS-APEO) n, 0.0158 g of catalyst, 0.0038 g of inhibitor and 0.1489 g of crosslinker were mixed together. The air bubbles were removed from the mixture and it was cross-linked in a hot press press for 15 minutes at 110 ° C and cured for 15 minutes at 110 ° C.

P r z k ł a d 9

An elastomeric membrane obtained from a Type I composition

Ingredients used to obtain an elastomeric membrane:

- PEO- (PDMS-PEO) n copolymer, in which the amount of PEO was 5.0% by weight and the content of vinyl groups was 0.04 mmol / g,

- DMS-VMS copolymer containing a silica filler, the same as in example 2,

- dichlorobenzoyl peroxide (Perkadox PD50 S).

The PEO- (PDMS-PEO) n copolymer was prepared as follows:

0.528 g of anhydrous α, ω-divinyl polyethylene oxide (PEODIVI) ether with a molecular weight of 240 g / mol was weighed into a three-necked flask. Additionally, 10 g of α, ω-bis (dimethylhydrosilyl) poly (dimethylsiloxane) (PDMSDIH) with a molar mass Mn = 6000 g / mol) were weighed into the same vessel. The content of hydride groups in PDMSDIH was 0.04% by weight and thus the amount of hydride groups in 10 g was 4 mmol and the amount of vinyl groups in PEODIVI was 4.4 mmol. Since the vinyl groups were present in excess (10 mol%) in the reaction, the final product was obtained with vinyl groups at both ends, which was important for the subsequent cross-linking. In addition, toluene dried by distillation was added to the reaction mixture to facilitate stirring and to prevent the reaction from proceeding too vigorously, so that the toluene ratio was 30% by weight (4.5 g). The reaction solution was mixed on a magnetic stirrer plate at 200 rpm and dried oxygen was simultaneously passed through the solution to prevent the catalyst from converting to a metallic form and thus prevent catalyst deactivation. The reaction solution was heated to 50 ° C and then the catalyst (Pt (0) divinyl tetramethyldisiloxane complex) was added to the solution through the septum. The amount of platinum was 50 ppm, calculated from the amount of the starting materials. The catalyst was added dropwise to avoid hot spots forming in the reactor. The reaction was run for 2 hours after the catalyst was added. Thereafter, completion of the reaction was confirmed by IR (loss of Si-H peak at 2130 cm ^-1 ). After completion of the polymerization, the reaction mixture was heated to 65 ° C and toluene was removed by vacuum distillation (5 mbar) over 30 minutes.

The amounts of ingredients in the composition of this example were as follows:

- PEO- (PDMS-PEO) n 4.9% by weight,

- DMS-YMS copolymer containing 93.9% by weight of silica filler,

- dichlorobenzoyl peroxide (Perkadox PD50 S) 1.2% by weight.

0.5 g of PEO- (PDMS-PEO) n and 9.5 g of a DMS-VMS copolymer containing a filler were mixed together. This homogeneous mixture was mixed with 0.12 g of a peroxide catalyst and obtained

The mixture was hardened for 5 minutes at the temperature of + 115 ° C and the pressure of 20 MPa and cross-linked for 2 hours at the temperature of + 150 ° C.

P r z k ł a d 10

An elastomeric membrane obtained from a J-type composition

Ingredients used to obtain an elastomeric membrane:

- PDMS-PEO graft copolymer, the same as in example 6,

- Dichlorobenzoyl peroxide, Perkadox PD50 S.

The amounts of ingredients in the composition of this example were as follows:

- PDMS-PEO graft copolymer 98.8% by weight

- dichlorobenzoyl peroxide Perkadox PD50 S 1.2% by weight.

10 g of the PDMS-PEO graft copolymer and 0.12 g of Perkadox PD50 S were mixed together. The obtained mixture was hardened for 5 minutes at the temperature of + 115 ° C and the pressure of 20 MPa and cross-linked for 2 hours at the temperature of +150 ° C.

Various devices for the release of agents with anti-progestogenic properties are illustrated in the following examples. These examples demonstrate modified drug release from various elastomer matrices and membranes. Various types of elastomer compositions (A-C, E and G) and poly (dimethylsiloxane-co-vinylmethylsiloxane) were used in the formulations of these examples, with or without silica filler.

P r x l a d 11

The implants described in this example as well as in example 13 consist of three parts: a drug-containing core in a polymer matrix, a membrane covering the core, and silicone end caps.

a) Implant based on a new elastomer composition containing an agent with antiprogestogenic properties

The implant comprises two different types of elastomer composition (B and E) and poly (dimethylsiloxane-co-vinylmethylsiloxane). This implant corresponds to device 2 in Fig. 1.

Membrane

In a twin roll mill, 26 parts of elastomer composition B, 71 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane) with silica filler, 10 ppm of catalyst (the nature of which depends on the reaction), 0.03 parts of inhibitor (ethynylcyclohexanol) and about 2 parts of crosslinker were mixed. poly (methylhydrogen siloxane-co-dimethylsiloxane). The mixture was extruded into 0.2 mm wall tubes and crosslinked by heating.

Core

In a twin roll mill, 29 parts of the E-type elastomer composition, 29 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm of the catalyst (the nature of which depends on the reaction), 0.02 parts of inhibitor (ethynylcyclohexanol) and about 2.4 parts of crosslinker were mixed - poly (methylhydrogen siloxane-co-dimethylsiloxane) and then 39 parts of the antiprogestogenic agent designated as compound 4 in Table 2 was added. The mixture was cast into PTFE-coated stainless steel molds which were heated for 30 minutes at + 115 ° C. The cores were removed, cooled and cut to the desired length (5 mm).

Receiving the implant

The membrane tubes (50 mm long) were swelled with cyclohexane and the cores were inserted into them. The obtained elements were allowed to evaporate the cyclohexane and then the ends were closed with a silicone adhesive. After 24 hours, the ends were cut to give 2 mm long end caps.

b) Implant based on a new elastomer composition containing an agent with anti-progestogenic properties

This implant was the same as that described in a) above, except that the length of the core was 13 mm. This implant corresponds to device 3 in Fig. 1.

c) Implant made with PDMS containing an agent with anti-progestogenic properties

Membrane

The silicone membrane corresponds to a commercial poly (dimethylsiloxane) membrane with silica filler and was made as follows:

In a two-roll mill, 99 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm of the catalyst (the type of which depends on the reaction), 0.03 parts of the inhibitor (ethynylcyclo) were mixed together.

Hexanol) and about 0.6 parts of the poly (methylhydrogen siloxane-co-dimethylsiloxane) crosslinker. The mixture was extruded into a tube with a wall thickness of 0.2 mm and crosslinked in an impingement oven. The tubular membrane was cut into lengths of 50 mm.

Core

In a two-chamber mixer 59.3 parts of commercial poly (dimethylsiloxane-co-vinylmethylsiloxane), 0.4 parts of crosslinking agent - poly (methylhydrogen siloxane-co-dimethylsiloxane), 0.02 parts of inhibitor (ethynylcyclohexanol) and 10 ppm of catalyst (which type depends on from reaction). Then 40 parts of an agent with antiprogestinic properties, designated as compound 4 in Table 2 below, were added, and the mixture was mixed in a two-chamber mixer. The mixture was poured into PTFE-coated stainless steel molds which were heated for 30 minutes at + 115 ° C. The cores were removed, cooled and cut to the desired length (5 mm).

Receiving the implant

The membrane tubes (50 mm long) were swelled with cyclohexane and the cores were inserted into them. The obtained elements were allowed to evaporate the cyclohexane and then the ends were closed with a silicone adhesive. After 24 hours, the ends were cut to give 2 mm long end caps. This implant corresponds to device 11 in Fig. 1.

P r z k ł a d 12

The intrauterine device (IUD) described in this example and in Examples 14 and 15 consists of three parts: a drug core contained in a polymer matrix, a membrane covering the core, and a T-shaped polyethylene body with a core covered with a membrane around it. .

a) IUD based on a new elastomer composition containing an agent with anti-progestogenic properties

IUD contains two different types of elastomer compositions (B, E) and poly (dimethylsiloxane-covinylmethylsiloxane). This implant corresponds to device 5 in Fig. 2.

Membrane

The membrane was the same as the membrane in example 11a.

Core

In a twin roll mill, 29 parts of the E-type elastomer composition, 29 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm of platinum catalyst (the nature of which depends on the reaction), about 0.02 parts of inhibitor (ethynylcyclohexanol) and about 2.4 parts of the agent were mixed together. crosslinking poly (methylhydrogen siloxane-co-dimethylsiloxane) and then added 39 parts of the agent with antiprogestogenic properties, indicated below in Table 2 as Compound 4.

The mixture was extruded into a 0.8 mm wall thickness tube and crosslinked by heating. The cores were cooled and cut into desired lengths (19 mm).

Receiving the IUD

The membrane tubes (50 mm long) and the cores were swelled with cyclohexane, placed on the polyethylene body of the T-shaped device, and cyclohexane was allowed to evaporate.

b) IUD obtained with PDMS containing an agent with anti-progestogenic properties

Membrane

The membrane was the same as described above in Example 11 c).

Core

100 parts of commercial poly (dimethylsiloxane-co-vinylmethylsiloxane), 0.4 parts of crosslinker - poly (methylhydrogen siloxane-co-dimethylsiloxane), 0.02 parts of inhibitor (ethynylcyclohexanol) and 0.06 parts of platinum catalyst in vinylmethylsiloxane) were mixed in a two-chamber mixer. . Then, 67 parts of an agent with anti-progestogenic properties, designated as compound 4 in Table 2 below, were added, and the mixture was mixed in a two-chamber mixer. The mixture was poured into PTFE-coated stainless steel molds which were heated for 30 minutes at + 115 ° C. The cores were removed, cooled and cut to the desired length (19 mm).

IUD

The membrane tubes (50 mm long) and the cores were swelled with cyclohexane, placed on the polyethylene body of the T-shaped device, and cyclohexane was allowed to evaporate. This implant corresponds to device 4 in Fig. 2.

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P r x l a d 13

a) Implant based on a new elastomer composition containing an agent with anti-progestogenic properties

The implant comprises two different types of elastomer composition (B and E) and poly (dimethylsiloxane-co-vinylmethylsiloxane). This implant corresponds to the device 7 in Fig. 3.

Membrane

The membrane was the same as described in example 11 a).

Core

In a twin roll mill, 50 parts of the E-type elastomer composition, 50 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm of platinum catalyst (the nature of which depends on the reaction), 0.02 parts of inhibitor (ethynylcyclohexanol) and approximately 2.4 parts of crosslinker were mixed. - poly (methylhydrogen siloxane-co-dimethylsiloxane). Then 67 parts of the antiprogestin agent designated as compound 1 in Table 2 below were added. The mixture was poured into PTFE-coated stainless steel molds which were heated for 30 minutes at + 115 ° C. The cores were removed, cooled and cut to the desired length (15 mm).

Receiving the implant

The membrane tubes (50 mm long) were swelled with cyclohexane and the cores were inserted into them. The obtained elements were allowed to evaporate the cyclohexane and then the ends were closed with a silicone adhesive. After 24 hours, the ends were cut to give 2 mm long end caps.

b) Implant prepared with the use of PDMS containing an agent with anti-progestogenic properties

Membrane

The membrane was the same as that described in example 11 c).

Core

In a two-chamber mixer, 100 parts of commercial poly (dimethylsiloxane-covinylmethylsiloxane), 0.4 parts of cross-linker - poly (methylhydrogen siloxane-co-dimethylsiloxane), 0.02 parts of inhibitor (ethynylcyclohexanol) and 10ppm of platinum catalyst (the nature of which depends on the reaction) were mixed. in vinylmethylsiloxane). Then, 67 parts of an agent with antiprogestinic properties, designated as Compound 1 in Table 2 below, were added, and the mixture was mixed in a two-chamber mixer. The mixture was poured into PTFE-coated stainless steel molds which were heated for 30 minutes at + 115 ° C. The cores were removed, cooled and cut to the desired length (15 mm).

Receiving the implant

The membrane tubes (50 mm long) were swelled with cyclohexane and the cores were inserted into them. The obtained elements were allowed to evaporate the cyclohexane and then the ends were closed with a silicone adhesive. After 24 hours, the ends were cut to give 2 mm long end caps. The implant corresponds to device 6 in Fig. 3.

P r z k ł a d 14

a) IUD based on a new elastomer composition containing an agent with anti-progestogenic properties

The IUD contains two different types of elastomer composition (B, E) and poly (dimethylsiloxane-co-vinylmethylsiloxane). This implant corresponds to device 9 in Fig. 4.

Membrane

The membrane was the same as the membrane described in Examples 11 a) and 12 a).

Core

In a twin roll mill, 50 parts of the E-type elastomer composition, 50 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm of platinum catalyst (the nature of which depends on the reaction), about 0.02 parts of inhibitor (ethynylcyclohexanol) and about 2.4 parts of the agent were mixed together. crosslinker - poly (methylhydrogen siloxane-co-dimethylsiloxane) and then 67 parts of the anti-progestogenic agent indicated below in Table 2 as Compound 1 was added. The mixture was extruded into a 0.8 mm wall tube and crosslinked by heating. The cores were cooled and cut into desired lengths (19 mm).

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Receiving the IUD

The membrane tubes (50 mm long) and the cores were swelled with cyclohexane, placed on the T-shaped polyethylene body of the device, and cyclohexane was allowed to evaporate.

b) IUD obtained with PDMS containing an agent with anti-progestogenic properties

Membrane

The membrane was the same as described above in Example 11 c).

Core

In a two-chamber mixer, 100 parts of commercial poly (dimethylsiloxane-covinylmethylsiloxane), 0.4 parts of poly (methylhydrogen siloxane-co-dimethylsiloxane) crosslinker, 0.02 parts of inhibitor (ethynylcyclohexanol) and 0.06 parts of platinum catalyst in vinylmethylsiloxane) were mixed. Then, 67 parts of an agent with antiprogestinic properties, designated as Compound 1 in Table 2 below, were added, and the mixture was mixed in a two-chamber mixer. The mixture was poured into PTFE-coated stainless steel molds which were heated for 30 minutes at + 115 ° C. The cores were removed, cooled and cut to the desired length (19 mm).

IUD

The membrane tubes (50 mm long) and the cores were swelled with cyclohexane, placed on the polyethylene body of the T-shaped device, and cyclohexane was allowed to evaporate. This implant corresponds to device 8 in Fig. 4.

P r z k ł a d 15

a) IUD based on a new elastomer composition containing an agent with anti-progestogenic properties

The IUD was the same as the IUD described in Example 14 a) except that the antiprogestin agent was compound 2 listed in Table 2 and the core length was 15 mm. This implant corresponded to device 11 in Fig. 5.

b) IUD obtained with PDMS containing an agent with anti-progestogenic properties

The IUD was the same as the IUD described in Example 14 b) except that the antiprogestin agent was compound 2 listed in Table 2 and the core length was 15 mm. This implant corresponded to device 10 in Fig. 5.

Permeation tests with membranes made of the new elastomer composition

From the above-mentioned compositions of the A-J type, various compositions were obtained in which the number of PEO groups was changed. Type A-B compositions have been tested for the permeation rate of certain agents with antiprogestinic properties.

The assay uses the assay apparatus described in Yie W. Chien, Transdermal Controlled System Medications, Marcel Dekker Inc., New York and Basel, 1987, page 173.

Drug flow (permeation) through the membranes was measured in a two-part diffusion cell at 37 ° C (Side-Bi-Side ™ diffusion cell, Crown Glass Company). The apparatus consisted of two concentric chambers which were separated by the elastomeric membrane under test. Both donor and receptor chambers were jacketed and thermostated using an external circulation bath, each chamber equipped with a magnetic stirrer. The drug solution and solvent (without drug) were introduced into the donor and receptor chambers. At predetermined time intervals, samples were taken from the receptor chamber and the defect was replaced with the same volume of solvent. The amount of drug permeated through the membrane was measured by HPLC. The membrane thickness (0.4 mm) and the surface area of the membranes were constant in all measurements.

In the tests described below, the permeation rates of two different drugs through a 0.4 mm thick elastomeric membrane were measured using the test apparatus described above. The following tables show the effect of PEO concentration (wt% in these compositions) on the permeation rates of various drugs for elastomers prepared from various types of compositions. The tables show the relative permeation compared to a commercial cross-linked dimethylsiloxane-vinylmethylsiloxane elastomer (Mn 400,000 g / mol) containing silica filler.

The compounds listed in Table 2 were subjected to this permeation test.

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T a b e l a 2

Agents with antiprogestogenic properties subjected to permeation tests

Number relationship Chemical name 1 4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11e-yl] benzaldehyde-1- (E) -oxime 2 4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- [O- - (ethylamino) carbonyl] oxime 3 11 e- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1 (E) - [O- - (ethylthio) carbonyl] oxime 4 11 e- (4-acetylphenyl) -17e-hydroxy-17a- (1,1,2,2,2-pentafluoroethyl) estra-4,9-dien-3-one 5 11 - [(4-dimethylamino) phenyl)] - 17-hydroxy-17- (3-hydroxy-1-propenyl) estr-4-en-3-one, [11 β, 17β, 17 (Ζ)] - (9-ΟΙ) 6 (Z) -6 '- (4-cyanophenyl) -17e-hydroxy-17a- (3-isovaleryloxy-1-propenyl)) - 4'H-naphtho- [3' ₁ 2 ^, 11 ': 10 ₁ 9 ₁ 11 ] _estra-4-one 15-dien-3-one

Permeation test results Compound 1

Relationship 1

Composition type PEO concentration [% w / w] Penetration relative reference 0 1 AND 4.7 3.5 AND 5.1 5.3 Relationship 2 Composition type PEO concentration [% w / w] Penetration relative reference 0 1 AND 4.7 4.1 AND 5.1 7.6 B 3.1 3.7 B 4.1 4.1 B 5.0 5.8 B 7.5 11.5 B 9.8 17.3 Relationship 3 Composition type PEO concentration [% w / w] Penetration relative reference 0 1 B 1.4 2.1 B 9.8 6.4

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Relationship 4 Composition type PEO concentration [% w / w] Penetration relative reference 0 1 B 7.5 16.4 B 9.8 27.6 Compound 5 Composition type PEO concentration [% w / w] Relative permeation reference 0 1 AND 4.7 4.1 B 3.1 6.0 B 4.1 6.7 B 5.0 10.7 B 7.5 18.7 B 9.8 37.2 Compound 6 Composition type PEO concentration [% w / w] Penetration relative reference 0 1 AND 4.7 2.9 AND 5.1 5.9

Permeation tests performed showed that increasing the concentration of PEO in the membrane resulted in an increase in the permeation rate for each type of composition and each drug tested.

Device release drug testing (implants or IUD devices)

The rate of drug release from the implant or IUD was measured in vitro as follows:

The implants or IUDs were attached to the stainless steel holders in an upright position and then the holders with the implants were placed in glass bottles containing 75 ml of dissolving agent. The glass bottles were shaken in a shaking water bath at 37 ° C. At predetermined time intervals, the dissolving agent was removed and replaced with fresh dissolving agent, and the drug release was analyzed by HPLC. The concentration of the dissolving agent and the time of exchange (removal and replacement) were chosen such that the starting conditions were maintained during the test.

The in vitro daily drug release from the devices is shown in Fig. 1 - Fig. 5. The experiments clearly showed an increased release rate when used on matrices and membranes for an elastomer composition containing poly (alkylene oxide) groups in a polysiloxane.

Claims (14)

Patent claims 1. A device for the controlled release over an extended period of time of a medicament having anti-progestogenic properties, which device comprises: - a core containing this drug, - optionally a membrane surrounding said core, wherein the core and / or the membrane are made of a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer, the elastomer composition being The PL 201 216 B1 comprises poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer or polymer as alkoxy terminated strains of polysiloxane units or as blocks, said strains or blocks being attached to the polysiloxane units via linkages silicon carbon or a mixture of these forms, characterized in that the antiprogestagens are compounds selected from the group consisting of: 11e - [(4- (dimethylamino) phenyl] -17e-hydroxy-17a- (1-propynyl) estra-4,9-diene-3-one (mifepristone), 11e - [(4- (dimethylamino) phenyl) -17e-hydroxy-17a- (1-propynyl) -18-homoestra-4,9-dien-3-one, 11 e - [(4- (dimethylamino) phenyl] -17e-hydroxy-17a- (1-propynyl) -17a-homoester-4,9,16-trien-3-one, 11e - [(4-dimethylamino) phenyl] -17a-hydroxy-17e- (3-hydroxypropyl) -13a-methylestra-4,9-dien-3-one (onapristone), (Z) -11e - [(4-dimethylamino) phenyl)] - 17e- hydroxy-17a- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one (lylopristone), 11 e- (4-acetylphenyl) -17e-hydroxy-17a- (1-propynyl) -estra-4,9-dien-3-one, (Z) -11e- (4-acetylphenyl) -17e-hydroxy-17a - (3-hydroxy-1-propenyl) estra-4,9-dien-3-one, 11 e- (4-methoxyphenyl) -17e-hydroxy-17a-ethynyl estra-4,9-dien-3-one, (Z) -11e - [(4-dimethylamino) phenyl)] - 17e-hydroxy-17a- ( 3-hydroxy-1-propenyl) estr-4-en-3-one, 4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) -oxime, 4- [17e-hydroxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) -oxime, 4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethylamino) carbonyl] oxime, 4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethoxy) carbonyl] oxime, 4- [17e-methoxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethylthio) carbonyl] oxime, 4- [17β-methoxy-17a- (ethoxymethyl) -3-oxoester-4,9-dien-11-yl] benzaldehyde-1- (E) - [O- (ethylthio) carbonyl] oxime, 4- [17e-hydroxy-17a- (methoxymethyl) -3-oxoester-4,9-dien-11e-yl] benzaldehyde-1- (E) - [O- (n-propylthio) carbonyl] oxime, (Z) -6 '- (4-cyanophenyl) -9,11a-dihydro-17e-hydroxy-17a- [4- (1-oxo-3-methylbutoxy) -1-butenyl) -4'H-naphtho- [3', 2 ', 1': 10,9,11] ester-4-en-3-one, (Z) -6 '- (4-cyanophenyl) -9.11 a-dihydro-17e-hydroxy-17a- [3 - (1-oxo-3-methylbutoxy) -1-propenyl) -4'H-naphtho [3 ', 2', 1 ': 10.9.11] estra-4,15-diene-3- one, (Z) -6 '- (4-cyanophenyl) -9.11a-dihydro-17e-hydroxy-17a- (3-hydroxy-1-propenyl) -4'H-naphtho [3', 2 ', 1 ': 10,9,11] estra-4,15-dien-3-one, (Z) -6' - (3-pyridinyl) -9.11a-dihydro-17e-hydroxy-17a- (3-hydroxy- 1-propenyl} -4'H-naphtho [3 ', 2', 1 ': 10.9.11] estra-4,15-dien-3-one, 11 e- (4-acetylphenyl) -17e-hydroxy-17a- (1,1,2,2,2-pentafluoroethyl) estra-4,9-dien-3-one, 6 '- (acetyloxy) -9.11 a-dihydro-17e-hydroxy-17a- (1,1,2,2,2-pentafluoroethyl) -4'H-naphtho- (3 ', 2', 1 ': 10,9,11] -ester-4 -en-3-on, 9,11a-dihydro-17e-hydroxy-6 '- (hydroxymethyl) -17a- (1,1,2,2,2-pentafluoroethyl) -4'H-naphtha [3', 2 ', 1': 10, 9,11] -ester-4-en-3-one, 11 e- {4-acetylphenyl) -19,24-dinor-17,23-epoxy-17a-chola-4,9,20-trien-3-one, 11 e- (4-methoxyphenyl) -19,24-dinor-17,23-epoxy-17a-chola-4,9,20-trien-3-one, (Z) -11e, 19- [4- ( 3-pyridinyl} -o-phenylene) -17e-hydroxy-17a- [3-hydroxy-1-propenyl) -4-androsten-3-one, (Z) -11e, 19- [4- (4-cyanophenyl } -o-phenylene) -17e-hydroxy-17a- [3-hydroxy-1-propenyl) -4androstene-3-one, 11 e- (4- (1-methylethenyl) phenyl] -17a-hydroxy-17e- (3-hydroxypropyl) -13a-estra-4,9-dien-3-one, 11 e- [4- (3-furanyl) phenyl] - 17a-hydroxy-17e- (3-hydroxypropyl) -13a-estra-4,9-dien-3-one, 4 ', 5'-dihydro-11e- [4- (dimethylamino) phenyl] -6e-methylspiro [estra-4,9-diene-17e, 2' (3'H) -furan] -3-one, 4 ', 5'-dihydro-11e- [4- (dimethylamino) phenyl] -7e-methylspiro [estra-4,9-diene-17e, 2' (3'H) -furan] -3-one, 4-e, 17a-dimethyl-17e-hydroxy-3-oxo-4a, 5-epoxy-5a-androstane-2a-carbonitrile, 7a- [9- (4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -trien-3,17e-diol, 3- (4-chloro-3-trifluoromethylphenyl) -1- (4-iodobenzenesulfonyl) -1,4,5,6-tetrahydropyridazine, (R, S) -3- (4-chloro-3-trifluoromethylphenyl) -1- (4-iodobenzenesulfonyl) -6-methyl-1,4,5,6-tetrahydropyridazine, 3- (3,4-dichlorophenyl) -1- (3,5-dichlorobenzoyl) -1,4,5,6-tetrahydropyridazine, PL 201 216 B1 3- (3,4-dichlorophenyl) -1- (2,5-dichlorobenzenesulfonyl) -1,4,5,6-tetrahydropyridazine, 7,8-dibromo-3,4-diazo-1,2,3,10,10a-hexahydro-3- (4-iodobenzenesulfonyl) phenanthrene, and 7-chloro-3,4-diazo-1,2,3,9,10,10a-hexahydro-3- (2,5-dichlorobenzenesulfonyl) phenanthrene. 2. The device according to claim Wherein the core is an elastomeric matrix, optionally made of an elastomer composition as defined in claim 1, 1. 3. The device according to claim 1 2. The process of claim 2, wherein the membrane or matrix is made of an elastomer based on polysiloxane units containing poly (alkylene oxide) groups. 4. The device according to claim 1 The process of claim 1, wherein the poly (alkylene oxide) groups in the elastomer composition are poly (ethylene oxide) groups (PEO groups). 5. The device according to claim 1 3. The polysiloxane groups of claim 1, wherein the polysiloxane groups are defined by the formula: (SiR'RO) qSiR'R where some of R 'and R are: - free groups which are the same or different, such as lower alkyl or phenyl in which case the alkyl or phenyl may be substituted or unsubstituted or a polyalkylene oxide group with terminal alkoxy groups of the formula -R3-O- (CHR -CH2-O) m-alk, in which alk is lower alkyl, suitably methyl, R is hydrogen or lower alkyl, R3 is C2-6-straight or branched alkylene and m is from 1 to 30; - bonds formed between a hydrogen atom or an alkenyl group and another polymeric chain in the elastomer; - optionally unreacted groups such as hydrogen, vinyl and alkenyl terminated vinyl; and q is a number from 1 to 3000. 6. The device according to claim 1 5. The process as claimed in claim 5, characterized in that the free groups R 'and R are lower alkyl, preferably methyl. 7. The device according to claim 1 2. The process of claim 1, wherein the poly (alkylene oxide) groups are present in the elastomer in the form of poly (alkylene oxide) blocks having the formula: -R3O (CHRCH2O) mR4 or -CH2CHR1COO (CHRCH2O) mCOCHR1CH2 in whose formulas: R is hydrogen, lower alkyl or phenyl, R 1 is hydrogen or lower alkyl, R3 and R4 are the same or different straight chain or branched C2-6 alkylene groups and m is from 1 to 30. 8. The device according to claim 1 The method of claim 1, wherein the elastomer composition is made of two elastomers that intertwine with each other, in which case: - the first elastomer comprises poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer as strains of end-alkoxy end-containing polysiloxane units or as blocks, said strains or blocks being attached to the polysiloxane units via silicon bonds carbon or a mixture of these forms; and - the second elastomer is a siloxane based elastomer. 9. The device according to claim 1 8. The process of claim 8, wherein the second elastomer is a poly (dimethylsiloxane) based elastomer which optionally contains polyalkylene oxide groups. 10. The device according to claim 1 9. The process of claim 9, wherein the optional poly (alkylene oxide) groups of the poly (dimethylsiloxane) based elastomer are present in the form of strains of polysiloxane units having an alkoxy end group or as blocks, in which case said strains or blocks are attached to the polysiloxane units via silicon-carbon bonds or a mixture of these forms. 11. The device according to claim 1 The process of claim 1, wherein the elastomer composition is a blend which comprises: - a siloxane based elastomer; and - a linear polysiloxane copolymer which comprises poly (alkylene oxide) groups, in which case the poly (alkylene oxide) groups are present in the polymer in the form of strains of polysiloxane units containing an end alkoxy group or as blocks, said strains or blocks being attached to polysiloxane units through silicon-carbon bonds or as a mixture of these forms. PL 201 216 B1 12. The device according to claim 1, The method of claim 2, wherein the matrix is enclosed in the membrane. 13. The device according to claim 1, 12. The process of claim 12, wherein both the matrix and the membrane are made of an elastomer composition containing poly (alkylene oxide) groups, which poly (alkylene oxide) groups are present in the elastomer or in the polymer as strains of end-alkoxy end-containing polysiloxane units or as blocks wherein said strains or blocks are attached to the polysiloxane units via silicon-carbon bonds or as a mixture of these species. 14. The device according to claim 1 The device of claim 1, wherein the device is an implant, an intrauterine or intracervical device, an intravaginal or a transdermal device. Drawings